Mammalian cells selected for resistance to certain antitumor drugs often display cross resistance to other apparently unrelated drugs and are thus said to display a multidrug resistant (MDR) phenotype (Bradley et al., Cancer Metastasis Rev., 1994, 13, 223). One form of the MDR phenotype is based on overexpression of one or more members of a family of membrane proteins (P-glycoproteins) which serve as ATP driven drug efflux pumps (Bradley et al., Cancer Metastasis Rev., 1994, 13, 223; Gottesman et al., J. Biol. Chem., 1988, 263, 12163; Roninson, Biochem. Pharmacol., 1992, 43, 95). The human MDR (P-glycoprotein) gene family has two members, only one of which (P170, encoded by the MDR1 gene) appears to be responsible for resistance to cytotoxic drugs (Roninson, Biochem. Pharmacol., 1992, 43, 95). In highly drug-resistant cells, P-glycoprotein message and protein levels can be many times greater than in their drug sensitive counterparts. Although MDR can be modulated by using a variety of agents that competitively inhibit P-glycoprotein mediated antitumor drug efflux (Kaji et al., Biochem., 1994, 33, 5041), several of these agents have proven less than ideal in clinical trials (Chabner et al., J. Clin. Oncol., 1991, 9, 4). Attempts have been made to utilize a ribozyme approach to modulation of the MDR phenotype (Kiehntopf et al., EMBO J., 1994, 13, 4645; Kobayashi et al., Cancer Res., 1994, 54, 1271; Scanlon et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 11123). In these efforts, however, ribozymes were introduced into cells by transfection, and clones were selected that had substantial levels of ribozyme expression. In these selected clones, a substantial impact on MDR1 mRNA and protein expression was observed. It remains to be seen whether the ribozyme approach offers a viable modality for modulating MDR expression in cell populations or tissues.
Chen et al. (J. Biol. Chem., 1990, 265, 506) describe the genomic organization and nucleotide sequence of a human MDR1 gene.
Vasanthakumar et al. (Cancer Commun., 1989, 1, 225) describe partial modulation of MDR1 expression, and a partial decrease in drug resistance, by methylphosphonate oligonucleotides complementary to the MDR1 gene. Neither cholesterol conjugates nor 2'-methoxyethoxy derivatives of such oligonucleotides are disclosed by Vasanthakumar et al.
Corrias et al. (Anticancer Res., 1992, 12, 1431) describe unmodified oligonucleotides that modulate MDR1 expression in cultured human adenocarcinoma cell lines. Neither cholesterol conjugates nor 2'-methoxyethoxy derivatives of such oligonucleotides are disclosed by Corrias et al.
Thierry et al. (Biochem. Biophys. Res. Commun., 1993, 190, 952) describe partial modulation of MDR1 expression by methylphosphonate oligonucleotides complementary to the 5' end of the coding region of the MDR1 gene. Neither cholesterol conjugates nor 2'-methoxyethoxy derivatives of such oligonucleotides are disclosed by Thierry et al.
Efferth et al. (Oncol., 1993, 50, 303) describe modulation of P-glycoproteins in cell lines derived from patients with kidney tumors by monoclonal antibodies, immunotoxins and a phosphorothioate antisense oligonucleotide targeted to nucleotides -9 to +6 of the MDR1 gene. Neither cholesterol conjugates nor 2'-methoxyethoxy derivatives of the oligonucleotide are disclosed by Efferth et al.
Palfner et al. (Biol. Chem. Hoppe-Seyler, 1995, 376, 289) describe in vitro studies of hammerhead ribozymes capable of cleaving MDR1 mRNA molecules.
Ho et al. (Nucl. Acids Res., 1996, 24, 1901) describe phosphothioate oligonucleotides that modulate RNase H activity on MDR1 RNA molecules transcribed in vitro. Neither cholesterol conjugates nor 2'-methoxyethoxy derivatives of such oligonucleotides are disclosed by Ho et al.
International Publication No. WO/9602556(A2) by Smyth describes antisense oligonucleotides to two portions of the MDR1 gene that encode nucleotide binding polypeptide motifs. Neither cholesterol conjugates nor 2'-methoxyethoxy derivatives of such oligonucleotides are disclosed by Smyth.
U.S. Pat. No. 5,510,239 to Baracchini, Jr., et al. (issued Apr. 23, 1996) describes compositions and methods for the modulation of a multidrug resistance-associated protein, MRP, which is encoded by a different gene from the target of the present invention.
To date, there are no known therapeutic agents which effectively inhibit expression of MDR genes encoding P-glycoproteins. Consequently, there remains a need for compositions and methods that effectively inhibit expression of such genes.